PDGFRA D842V substitution mutation in advanced or metastatic GIST. The PDGFRA D842V varia...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-GIST-PDGFRA-D842V`
Type	Red flag
Status	reviewed 2026-05-08 \| pending_clinical_signoff
Diseases	`DIS-GIST`
Sources	`SRC-NAVIGATOR` `SRC-NCCN-GIST-2025` `SRC-VOYAGER`

Red Flag Origin

Definition	PDGFRA D842V substitution mutation in advanced or metastatic GIST. The PDGFRA D842V variant accounts for approximately 6-7% of all GIST and is the most common PDGFRA exon 18 mutation (~65-70% of PDGFRA-mutant GIST). D842V confers primary resistance to imatinib, sunitinib, and regorafenib due to steric interference with drug binding at the activation loop. The type I kinase inhibitor avapritinib binds the active conformation of PDGFRA D842V and achieves ORR ~88% (NAVIGATOR phase 1; Heinrich CANCER DISCOV 2020) and confirmed ORR ~91% in the phase 3 NAVIGATOR expansion cohort. Imatinib is ineffective (historical ORR <10% for D842V) and must not be used as 1L for confirmed D842V-mutant GIST. Fires to route ALGO-GIST-1L step 1 to avapritinib (IND-GIST-1L- AVAPRITINIB-PDGFRA-D842V) instead of imatinib (IND-GIST-1L-IMATINIB). NCCN GIST 2025 Category 1 preferred: avapritinib 300 mg PO QD for PD...
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-GIST-1L

Trigger Logic

{
  "any_of": [
    {
      "finding": "BIO-PDGFRA",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_mutation",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_exon18_mutation",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_mutation_codon",
      "value": "D842V"
    },
    {
      "finding": "pdgfra_d842v",
      "value": "true"
    }
  ],
  "type": "biomarker_status"
}

Notes

W5c RF authoring. Converts free-text `{condition: "PDGFRA D842V mutation positive"}` in ALGO-GIST-1L step 1 into a formal RF entity. Clinical rationale: PDGFRA D842V confers primary resistance to all approved TKIs except avapritinib. NAVIGATOR phase 3 expansion cohort (Heinrich et al, CANCER DISCOV 2020; trial NCT02508532) demonstrated ORR 88-91% with avapritinib 300 mg QD; median PFS not reached at data cutoff. VOYAGER (NCT03465722) was designed as avapritinib vs regorafenib in 3L+ GIST (mixed genotype); primary endpoint (PFS) did not meet statistical significance but was confounded by inclusion of non-D842V GIST. NAVIGATOR remains the key evidence base for D842V 1L. Trigger: uses BIO-PDGFRA/D842V pattern consistent with BMA entity bma_pdgfra_d842v_gist.yaml (ESCAT IA). Legacy finding name variants retained for backward engine compatibility until biomarker normalization pass completes. PDGFRA non-D842V exon 18 mutations (D842del, DI842-843IM, N659K, etc.) are NOT within this RF scope — those have intermediate imatinib sensitivity and route via ALGO-GIST-1L step 2 imatinib path. Source stubs: SRC-NAVIGATOR and SRC-VOYAGER are auto-stubs with pending citation verification (PMID + D...

Used By

Algorithms

ALGO-GIST-1L - ALGO-GIST-1L